This is a competitive renewal application to continue the study of mechanisms of vaccine efficacy against Streptococcus pneumoniae. Pneumococcal disease remains a cause of significant mortality and morbidity in patients with HIV infection, particularly in regions where HAART is not available, and could re-emerge as a major problem in those receiving HAART as they reach senescence. The importance of understanding mechanisms of vaccine efficacy against pneumococcus is heightened by the prevalence of drug-resistant isolates and concerns about the efficacy of licensed vaccines in immunocompromised adults and serotype replacement in vaccinated children. Available knowledge cannot predict whether vaccine-induced immune responses will be protective or the individuals who will be protected by vaccination. In the prior funding period my research program made the observation that although it did not promote opsonophagocytosis in vitro, the efficacy of a protective serotype-specific IgM was associated with modulation of the proinflammatory cytokine response to experimental pneumococcal challenge in mice. These findings challenged the current paradigm that links vaccine efficacy to opsonic antibody. The focus of this competing renewal application is on the antibody characteristics and host variables that govern vaccine efficacy against pneumococcal bacteremia and pneumonia. Our central hypothesis is that certain serotype-specific antibodies mediate protection by modulating the host inflammatory response to pneumococcal infection. We propose to validate or refute this hypothesis in mouse strains with defined cellular immune defects, which will allow us to precisely define the contributions of T and B cells to vaccine efficacy. Three Specific Aims are proposed: 1) To identify components of innate and cellular immunity required for vaccine efficacy against pneumococcal bacteremia and pneumonia; 2) To assemble a mechanistic framework of vaccine efficacy based on the nature of the Ab response and immune response of the host; and 3) To identify mechanisms of Ab efficacy against bacteremia and pneumonia and determine their dependency on the nature of the Ab and immune status of the host. We anticipate that the studies proposed herein will provide important new knowledge about the protective immune response to S. pneumoniae that will translate into identification of new correlates of vaccine efficacy and the generation of hypotheses for future testing in human studies.